Aging remains the single most important risk factor in human disease in North America and the idea that nutritional interventions can have profound effect on the onset of age-related disease is vitally important during a time of dramatic demographic change. Dietary restriction (DR), a reduction of nutrients in the diet, provides the most robust method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. It has been shown in rodents that DR protects against a number of age related diseases including Huntington's, cancer, diabetes and other cardiovascular diseases. Given the universally protective effects of DR, investigating its molecular mechanisms will promote a greater understanding of the pathogenesis of various human age related diseases, which will in turn help advance the development of therapeutics for these disorders. We have identified the conserved nutrient sensing TOR pathway as a critical regulator of DR dependent lifespan changes. Using a combination of biochemical, genetic and genomic technologies we propose to understand the link between TOR, metabolism and aging. We hypothesize that modulation of mRNA translation by the TOR pathway leads to alterations in ATP generating pathways and mitochondrial function which mediates the lifespan effects of the TOR pathway. This proposal will examine the conservation of the effects of the TOR modulation on mitochondrial function between flies and human cells. Furthermore, using Drosophila we shall examine the cause and effect relationship between ATP generating pathways and lifespan. RELEVANCE: There is considerable interest in nutritional interventions that decrease the risk of disease and extend healthy lifespan. Since there is a high degree of genetic homology between humans and model organisms such as flies and worms, we believe it is timely to understand the dietary factors that regulate lifespan and metabolism in these simple organisms. Our findings will have a significant impact on helping uncover the role of nutrition in the etiology of a number of age-related diseases like cancer and diabetes.